Visceral leishmaniasis (VL) poses a major health problem in northeastern Brazil. For decades VL was seen in Brazil primarily in rural areas, but recently it has occurred in urban areas such as the city of Natal, Rio Grande do Norte. Leishmania chagasi is the responsible pathogen. Our group, which includes investigators from three Brazilian and three US Universities, has collaboratively studied the clinical features, epidemiology, natural history and immunogenetics of L. chagasi infection. Study areas included first a rural endemic region of Ceara, and more recently the peri-urban areas near Natal where VL has been epidemic for > 10 years. Our data indicate a statistically significant clustering of L. chagasi infection in families, and a correlation between the pattern of disease and genetic relationships. Based on our findings, we hypothesize that both environmental and genetically determined immune responses govern the outcome of L. chagasi infection. The current proposal is designed to extend and amplify our initial findings in defining these determinants. The specific aims are as follows: (I) To expand the family cohort exposed to L. chagasi in the endemic area and to develop a sensitive and specific means of identifying prior asymptomatic self- resolving subclinical L. chagasi infection; (2) To identify candidate genes, alleles of which correlate significantly with different phenotypic manifestations of L. chagasi infection including life-threatening VL; (3) To identify the mechanism by which polymorphic alleles at candidate genetic loci affect the phenotypic manifestations of Leishmania infection. The initial focus will be directed toward alleles of Nrampl, IL-4 and TNFa loci, which in preliminary studies correlate with specific phenotypes. The availability of a large cohort of well characterized families exposed to L. chagasi in close proximity to the research facilities in Natal provides a unique opportunity to accomplish these aims. The resulting data will allow for the rational development of approaches to immunoprophylaxis and environmental control measures to protect residents of northeastern Brazil and other endemic areas against this life-threatening infection.